Journal of Physiology - Paris 107 (2013) 503–509

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Journal of Physiology - Paris

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PET neuroimaging of extrastriatal dopamine receptors and prefrontalcortex functions

0928-4257/$ - see front matter � 2013 Elsevier Ltd. All rights reserved.http://dx.doi.org/10.1016/j.jphysparis.2013.07.001

⇑ Tel.: +81 75 751 3386; fax: +81 75 751 3246.E-mail address: hidehiko@kuhp.kyoto-u.ac.jp

Hidehiko Takahashi ⇑Department of Psychiatry, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawara-cho, Sakyo-ku, Kyoto 606-8507, Japan

a r t i c l e i n f o a b s t r a c t

Article history:Available online 12 July 2013

Keywords:DopamineReceptorsPrefrontal cortexHippocampusPositron emission tomographyCognition

The role of prefrontal dopamine D1 receptors in prefrontal cortex (PFC) functions, including workingmemory, is widely investigated. However, human (healthy volunteers and schizophrenia patients) posi-tron emission tomography (PET) studies about the relationship between prefrontal D1 receptors and PFCfunctions are somewhat inconsistent. We argued that several factors including an inverted U-shapedrelationship between prefrontal D1 receptors and PFC functions might be responsible for these inconsis-tencies. In contrast to D1 receptors, relatively less attention has been paid to the role of D2 receptors inPFC functions. Several animal and human pharmacological studies have reported that the systemicadministration of D2 receptor agonist/antagonist modulates PFC functions, although those studies donot tell us which region(s) is responsible for the effect. Furthermore, while prefrontal D1 receptors areprimarily involved in working memory, other PFC functions such as set-shifting seem to be differentiallymodulated by dopamine. PET studies of extrastriatal D2 receptors including ours suggested that orches-tration of prefrontal dopamine transmission and hippocampal dopamine transmission might be neces-sary for a broad range of normal PFC functions. In order to understand the complex effects ofdopamine signaling on PFC functions, measuring a single index related to basic dopamine tone is notsufficient. For a better understanding of the meanings of PET indices related to neurotransmitters, com-prehensive information (presynaptic, postsynaptic, and beyond receptor signaling) will be required. Still,an interdisciplinary approach combining molecular imaging techniques with cognitive neuroscience andclinical psychiatry will provide new perspectives for understanding the neurobiology of neuropsychiatricdisorders and their innovative drug developments.

� 2013 Elsevier Ltd. All rights reserved.

1. Introduction

The prefrontal cortex (PFC) receives dense dopaminergic inputoriginating in the ventral tegmental area. Due to the fact that dopa-mine D1 receptors in PFC are several times more abundant than D2receptors (Hall et al., 1994), the roles of D1 receptors in PFC func-tions have been widely investigated. It has been demonstrated thatlocal administration of D1 receptor antagonists into PFC inducedimpairment in working memory task in non-human primate(Sawaguchi and Goldman-Rakic, 1991). In human, positron emis-sion tomography (PET) has been utilized to quantify prefrontalD1 receptors in vivo, and their role in human PFC functions hasbeen studied. In contrast to D1 receptors, initial PET studies ofD2 receptors were limited to the striatal region because of a lackof appropriate PET ligands for measuring D2 receptors outsidethe striatum where their expression is very low (Hall et al.,1994). With the introduction of high-affinity PET radioligands suchas [11C]FLB457 (Halldin et al., 1995) and [18F]-fallypride

(Mukherjee et al., 1996), it has become possible to quantify extra-striatal D2 receptors by PET. In this short review, we summarizePET studies investigating the role of extrastriatal dopamine D1and D2 receptors in PFC functions.

2. PET imaging of D1 receptors and PFC functions

2.1. PET imaging of prefrontal D1 receptors in schizophrenia

Because schizophrenia patients are known to have impairmentsof PFC functions including working memory and set-shifting(Kalkstein et al., 2010), prefrontal D1 receptors in schizophreniahave been investigated using PET. An initial PET study with[11C]SCH23390 revealed that D1 receptors in PFC were decreasedin schizophrenia, which was associated with poor performanceon the Wisconsin Card Sorting Test (WCST), a test requiring work-ing memory and set-shifting abilities (Okubo et al., 1997).However, another PET study using [11C]NNC112 reported that in-creased D1 receptors in PFC were associated with working memorydeficits in schizophrenia (Abi-Dargham et al., 2002). The same re-search group recently replicated increased D1 receptors in PFC of

504 H. Takahashi / Journal of Physiology - Paris 107 (2013) 503–509

drug-naïve schizophrenia patients. The interpretation was that theincrease is related to compensatory up-regulation in response tolower dopamine tone in PFC (Abi-Dargham et al., 2012). In supportof their interpretation, they investigated the effect of a functionalpolymorphism in the catechol O-methyltransferase (COMT) gene,which has been shown to modulate the prefrontal dopamine level,on prefrontal D1 receptors (Slifstein et al., 2008). The COMT genecontains a common polymorphism, a valine (Val)-to-methionine(Met) substitution at codon 158 (Val158Met). The Val allele is asso-ciated with higher activity, whereas the Met allele is associatedwith lower enzymatic activity (Lachman et al., 1996). Conse-quently, individuals with the val/val genotype have a lower levelof extracellular dopamine in PFC. Using [11C]NNC112 PET, theydemonstrated that individuals with the val/val genotype show sig-nificantly higher cortical D1 receptor binding than individuals withthe met/met genotype, suggesting a mechanism by which a lowerlevel of extracellular dopamine in PFC induces up-regulation of D1receptors in individuals with the val/val genotype (Slifstein et al.,2008).

It has been discussed that these inconsistent results might stemfrom differences in radioligands, but our more recent PET studymeasuring cortical D1 receptors with both [11C]SCH23390 and[11C]NNC112 in the same schizophrenia sample demonstrated thatprefrontal D1 receptors were decreased in chronic schizophreniaregardless of the radioligands used (Kosaka et al., 2010).

2.2. An inverted U-shaped relationship between prefrontal D1receptors and PFC functions

In order to partly reconcile the inconsistency that Okubo et al.(1997) (Abi-Dargham et al. (2002)) showed that too low (high) pre-frontal D1 receptors in schizophrenia were associated with poorPFC function, we focused on an inverted U-shaped relationship be-tween prefrontal D1 receptors and PFC functions (Takahashi et al.,2008b). A body of animal studies has indicated that stimulation ofD1 receptors in PFC produces an inverted U-shaped dose-responsecurve, such that too little or too much D1 receptor stimulation im-pairs PFC functions (Cools and D’Esposito, 2011; Goldman-Rakicet al., 2000; Williams and Castner, 2006). Primal animal studiesindicated that stimulation of D1 receptors in PFC produces an in-verted U-shaped response in working memory, with the responsebeing optimized within a narrow range of D1 receptor stimulation(Castner and Goldman-Rakic, 2004; Lidow et al., 2003; Seamansand Yang, 2004; Vijayraghavan et al., 2007). Subsequent humanstudies have investigated the effect of a functional polymorphismin the COMT gene on PFC functions. Individuals with the val/valgenotype show lower performance and increased (inefficient) PFCactivation during completion of cognitive tasks related to PFC func-tions (WCST and N-back task) (Egan et al., 2001; Goldberg et al.,2003). It was reported that amphetamine challenge in individualswith the val/val genotype induced improvement in the perfor-mance of WCST and decreased (efficient) PFC activation duringN-back task, whereas that in individuals with the met/met geno-type caused deterioration in the performance of WCST and in-creased (inefficient) PFC activation, indicating that too little ortoo much dopamine signaling would impair PFC functions,although these studies could not identify the receptor subtype thatplays a central role in this effect (Mattay et al., 2003).

We thought that this model might account for PFC function def-icits in schizophrenia patients, regardless of whether D1 receptorsin PFC are increased or decreased in patients. D1 receptor binding,indices proportional to receptor density, was measured using[11C]SCH23390 in healthy male subjects, and the relationship be-tween prefrontal D1 receptors and neurocognitive performanceincluding PFC functions was examined. Quadratic regressionanalysis was conducted to reveal the putative ‘‘U-shaped’’ relation

between D1 receptor binding in PFC and its functions. Althoughstandard linear regression analysis revealed a trend-level negativecorrelation between D1 receptor binding in PFC and total error ofWCST, a quadratic regression model better predicted the relation-ship (Takahashi et al., 2008b). That is, we found a significant ‘‘U-shaped’’ relationship between D1 receptor binding in PFC and totalerror of WCST (because total error of WCST is a negative measureof frontal lobe function, the relation is not ‘‘inverted’’) (Fig. 1).

An inverted U-shaped response has been suggested based oncognitive and behavioral studies (Williams and Castner, 2006),but the exact physiological mechanism of this effect has not yetbeen fully understood. A monkey electrophysiology study hasdemonstrated a neuron-level mechanism that constitutes the in-verted U-shaped response whereby too much or too little stimula-tion of prefrontal D1 receptors leads to working memory deficits(Vijayraghavan et al., 2007). D1 receptor stimulation had a sup-pressive effect on the PFC neural activities involved in a spatialworking memory task. Moderate D1 receptor stimulation spatiallytunes PFC neurons that process target signals by preferentially sup-pressing non-target (noisy) neural activities, whereas excessive D1receptor stimulation induces non-selective suppression of PFCneural activities irrespective of whether the neural activities aretask-related or not (Vijayraghavan et al., 2007). Supporting this no-tion, a PET study investigated the relation between cortical D1receptors and intra-individual variability, that is, within-personfluctuations in cognitive performance. The study reported thatage-related increase in intra-individual variability in performancewas associated with low-level cortical D1 receptors in aged sub-jects (MacDonald et al., 2012). Low-level cortical D1 receptorsmight lead to a decreased signal-to-noise ratio in the cortex, thenpossibly resulting in increased fluctuations in performance.

2.3. Other factors to be considered for measurement of prefrontal D1receptors in human

The inverted U-model is not a perfect explanation for the incon-sistent findings of D1 receptors and PFC dysfunction in schizophre-nia, and a recent PET study did not find linear or quadraticrelationships between D1 receptors in PFC and performance in cog-nitive tasks that are dependent on PFC (Karlsson et al., 2011). Moreimportantly, although the inverted U-model tells us that altered(extreme) prefrontal D1 receptors will lead to poor PFC functionsin schizophrenia regardless of whether prefrontal D1 receptorsare increased or decreased in schizophrenia, the model per se doesnot tell us why some studies reported decreased prefrontal D1receptors in schizophrenia (Okubo et al., 1997) and others reportedincreased (Abi-Dargham et al., 2002) or unchanged (Karlsson et al.,2002) prefrontal D1 receptors in schizophrenia. Thus, other factorsshould be considered to explain these inconsistencies. D1 receptorsare known to decrease with age in healthy controls (Kosaka et al.,2010). A recent study demonstrated that age-related reduction inD1 receptors in PFC was associated with age-related reduction inworking memory performance and PFC activation during workingmemory task (Bäckman et al., 2011). That study tells us that otherfactors besides D1 receptors, such as pre-synaptic dopamine syn-thesis and cerebrovascular pathology, could influence PFC func-tions and PFC activation in older adults, and interaction betweengroups (schizophrenia patients versus controls) and age, i.e.,illness-specific reduction in D1 receptors, should also be consid-ered. Thus, the design and performance of longitudinal studies ofprefrontal D1 receptors in schizophrenia are stronglyrecommended.

Furthermore, although [11C]SCH23390 and [11C]NNC112 areselective radioligands for D1 receptors, they have some affinityfor 5HT2A receptors. 5HT2A receptor density in the striatum isnegligible compared to D1 receptor density, whereas 5HT2A

Fig. 1. Quadratic (inverted U-shaped) relationship between D1 receptor binding in PFC and performance of WCST. ROI analysis revealed a significant quadratic regressionbetween D1 receptor binding in PFC and total error of WCST. Red solid line: quadratic regression, black broken line: linear regression (left panel). SPM analysis also revealedsignificant quadratic regression between prefrontal D1 receptor binding and total error of WCST (right panel).

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receptor density is not negligible in extrastriatal regions. Previousreports have indicated that their affinity for 5HT2A receptors rela-tive to D1 receptors is negligible. However, recent in vivo studiesreported that D1 to 5-HT2A selectivity of these radioligands wasin a range of approximately 5- to 14-fold and 10–25% of the corti-cal signals of these radiologands was due to binding to 5HT2Areceptors (Ekelund et al., 2007; Slifstein et al., 2007). Thus, cautiousinterpretation of the extrastriatal findings regarding these radioli-gands is recommended. Another related problem is that selectiveD1 agonist/antagonist is not available for human use. A body ofdata from animal studies supports the utility of the D1 agonistfor the treatment of cognitive impairments in schizophrenia (Bu-chanan et al., 2007). In human, a mixed D1 and D2 agonist, pergo-lide, was reported to have a positive effect on working memory(Müller et al., 1998). However, it is not clear whether this effectwas attributable to D1 receptor stimulation because the affinityof pergolide for D1 receptors is lower than for D2 receptors, andit was reported that it may not stimulate D1 receptors in vivo atdoses used to activate D2 receptors (Fuller and Clemens, 1991;Mehta and Riedel, 2006). More recently, a selective D1/D5 agonist,dihydrexidine, has been a target for improving cognitive deficit inschizophrenia (George et al., 2007; Mu et al., 2007). However, theefficacy of this compound on cognitive impairments has so farnot been proven due to several practical issues concerning drugdevelopment (poor oral bioavailability, short half-life, and adverseeffects) (Ye et al., 2013). For instance, George et al. (2007) reportedthat a single low dose of dihydrexidine administered subcutane-ously is safe and tolerated in patients with schizophrenia, but didnot produce delayed clinical or neuropsychological improvements.

However, the efficacy of D1 agonists on cognitive impairmentshas so far not been proven due to several practical issues concern-ing drug development. Not only clinical psychiatry but also basichuman neurosciences have been eagerly awaiting the developmentof selective D1 agonist/antagonist.

3. PET imaging of D2 receptors and PFC functions

3.1. Central D2 receptors stimulation and PFC functions

In contrast to D1 receptors, relatively less attention has beenpaid to the role of prefrontal D2 receptors in cognitive functionspartly because their density in extrastriatal regions is very low(Suhara et al., 1999). It was reported that blockade of D2 receptorsin PFC did not impair working memory in non-human primate(Sawaguchi and Goldman-Rakic, 1991). Müller et al. (1998)reported that the systemic administration of the mixed D1/D2

receptor agonist pergolide facilitated working memory while theselective D2 receptor agonist bromocriptine had no effect. How-ever, there is converging evidence from human and animal studiesto suggest the involvement of D2 receptors in cognitive functions.In an animal study, mice lacking D2 receptors were reported tohave a working memory deficit (Glickstein et al., 2002). It was re-ported that the systemic administration of bromocriptine in hu-man improved cognitive functions including working memoryand executive functions (Luciana et al., 1992; McDowell et al.,1998), and the administration of the D2 receptor antagonist sulpir-ide impaired those functions (Mehta et al., 1999). Moreover, phar-macological studies in human have shown that the effect ofsystemic bromocriptine administration depends on baseline work-ing memory capacity. Bromocriptine improved working memory inlow-capacity subjects, while impairing it in high-capacity subjects(Kimberg et al., 1997), suggesting that D2 receptor stimulation alsomight have inverted U-shaped action on PFC functions (Cools andD’Esposito, 2011). These studies, however, did not reveal the re-gions most responsible for these effects. Because the density ofD2 receptors in PFC is very low, D2 receptors outside the PFC couldbe candidates. The striatum, where D2 receptors are abundant, hasbeen a straightforward candidate, and the role of dopamine in thestriatum-PFC loop and PFC functions is widely acknowledged. Thistopic has been nicely reviewed elsewhere (Cools and D’Esposito,2011). Another potential substrate for the modulatory effects ofD2 agonist/antagonist is the hippocampus (HPC), based on the factthat the density of D2 receptors in the medial temporal cortex isrelatively high in the cortical regions (Suhara et al., 1999). In addi-tion to the PFC functions, systemic administration of D2 receptoragonist (antagonist) improved (impaired) episodic memory in old-er healthy human subjects (Morcom et al., 2010).

3.2. D2 receptors in HPC and PFC functions

While it is likely that prefrontal D1 receptors predominantlymodulate PFC functions, we hypothesize that the combination ofprefrontal D1 receptors and D2 receptor stimulation outside PFCis most effective. Therefore, in the aforementioned study(Takahashi et al., 2008b), we investigated extrastriatal D2 receptorbinding using [11C]FLB457 PET in the same sample. Neither linearnor quadratic relation was found between D2 receptor binding inPFC and any neuropsychological measures. However, in line withour previous study (Takahashi et al., 2007), we found that D2receptor binding in HPC was positively correlated not only withepisodic memory ability but also with WCST performance (Takah-ashi et al., 2008b) (Fig. 2).

Fig. 2. Linear relationship between D2 receptor binding in HPC and performance of WCST. ROI analysis revealed positive linear correlation between D2 receptor binding inHPC and total error of WCST (left panel). SPM analysis also revealed similar correlation between hippocampal D2 receptor binding and total error of WCST (right panel).

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Patients with lesions in HPC sometimes show deficits in WCST(Corkin, 2001; Igarashi et al., 2002). It was reported that infusionof the D2 receptor agonist quinpirole in HPC of rats improvedworking memory performance in the radial-arm maze, while ven-tral hippocampal infusion of the D2 receptor antagonist raclopridein HPC impaired performance (Wilkerson and Levin, 1999). Theseobservations suggest that hippocampal D2 receptors could modu-late PFC activity by the HPC–PFC pathway, which plays a signifi-cant role in the cognitive process (Laroche et al., 2000; Thierryet al., 2000). Accumulating evidence has suggested the modulatoryeffects of dopamine on HPC–PFC interactions (Goto and Grace,2008; Seamans et al., 1998; Tseng et al., 2007). Supporting theimportance of hippocampal D2 receptors in PFC functions, using[11C]FLB 457 PET, Aalto et al. (2005) demonstrated a reduction ofD2 receptor binding in HPC during working memory task com-pared to control condition, suggesting HPC D2 receptor stimulationduring working memory load. In addition, MacDonald et al. (2009)reported that lower D2 receptor binding in HPC was associatedwith greater intra-individual variability in episodic memory andexecutive function, indicating that lower D2 receptor-mediatedtransmission in HPC leads to noisy neural information processingand results in unstable episodic memory and executive functions.Recently, other PET studies reported the importance of prefrontalD1 receptors (Karlsson et al., 2011) or prefrontal D2 receptors(Ko et al., 2012) in executive functions.

WCST is a test for executive functions or PFC functions thatinclude working memory process and set-shifting (behavioral flex-ibility). Based on rat studies, Floresco and Magyar (2006) suggestedthat, while prefrontal D1 receptors are primarily involved in work-ing memory, comparative actions of D1 and D2 receptors are nec-essary for set-shifting. Furthermore, they noted that the ‘‘invertedU-shaped’’ relationship between prefrontal D1 receptors and PFCfunction is limited to working memory and does not necessarilyapply to other PFC functions such as set-shifting. Inhibitory GAB-Aergic inputs to pyramidal neurons in PFC were enhanced andattenuated through D1 receptor and D2 receptor activations,respectively (Seamans et al., 2001). It is expected that D1 and D2activations might contribute to making the PFC network stableand vulnerable, respectively (Seamans and Yang, 2004). In the pro-cess of set-shifting, one needs to disengage from the previousattentional set and represent multiple stimuli and strategies. Ani-mal studies and human PET findings including ours suggested thatorchestration of prefrontal dopamine transmission and hippocam-pal dopamine transmission might be necessary for a broad range ofnormal PFC functions.

4. PET imaging before and beyond receptors

4.1. Measurements of tonic and phasic dopamine transmission

First, for a better understanding of the role of dopamine in PFCfunctions, we should consider the fact that dopamine neurons areknown to show tonic (basic) firing and phasic (burst) firing andthat, in turn, tonic and phasic dopamine release is induced, respec-tively (Grace, 1991; Grace et al., 2007). Although the release ofboth tonic and phasic dopamine is necessary for PFC functions,phasic dopamine release plays a crucial role in working memoryand set-shifting (Braver et al., 1999; Phillips et al., 2004). StandardPET indices (dopamine receptors, dopamine transporters, dopa-mine synthesis) are related to dopamine transmission during rest-ing state without any cognitive load (Ito et al., 2011). These indicesare considered to reflect basic dopamine tone (Ito et al., 2008,2011). On the other hand, PET can be used for the indirect mea-surement of changes in synaptic dopamine concentration in vivo.[11C]raclopride has been used for measuring dopamine release inthe striatum in response to addictive drugs like cocaine, amphet-amine and nicotine (Dewey et al., 1993; Takahashi et al., 2008a)and even in response to cognitive load (Koepp et al., 1998). Dopa-mine is thought to compete with [11C]raclopride at the D2 recep-tor, and dopamine release is associated with a reduction in[11C]raclopride binding (Dewey et al., 1993). Because of its lowaffinity, [11C]raclopride is not suitable for measuring dopamine re-lease in the extrastriatal regions, where the D2 receptor density ismuch lower than in the striatum. High-affinity PET radioligandssuch as [11C]FLB457 and [18F]-fallypride were reported to be capa-ble of detecting dopamine release in the cortical regions byamphetamine challenge or cognitive task (Aalto et al., 2005;Buckholtz et al., 2010). However, several studies failed to detectthe expected effect in the cortical regions (Cropley et al., 2008; Slif-stein et al., 2010). This is thought to stem from the fact that the sig-nal-to-noise ratio of D2 receptor binding in the cortical regions isrelatively low even if high-affinity radioligands are used. Hence,indirect measures of dopamine release, a subtraction of bindingpotential between two (on and off) PET scans, are very sensitiveto noise (Lataster et al., 2013). Furthermore, careful considerationfor the timing of task or drug challenge is needed, because differentuptake and washout kinetics across various brain regions due tothe difference in receptor density would result in inconsistentresults across the brain regions (Ceccarini et al., 2012). In contrastto D2 receptors, D1 receptors are moderately expressed in thecortical regions, and both striatal and extrastriatal D1 receptors

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can be measured by a single D1 antagonist radioligand (Farde et al.,1987). However, D1 antagonist radioligands such as[11C]SCH23390 and [11C]NNC112 (Abi-Dargham et al., 1999) arenot sensitive to endogenous dopamine release even in the stria-tum. It is conceivable that several factors contribute to the insensi-tivity of D1 receptors to the dopamine concentration in thesynaptic cleft, but the exact reasons for the insensitivity are asyet unknown. It has been shown that D1 receptors have much lessaffinity for endogenous dopamine than D2 receptors (Richfield etal., 1989). Furthermore, cortical and striatal D1 receptors areknown to be predominantly extrasynaptic (Smiley et al., 1994;Caille et al., 1996). Thus, it is difficult to measure prefrontal D1receptor stimulation by phasic dopamine release during workingmemory or set-shifting. Recently, McNab et al. (2009) investigatedthe effect of intensive working memory training on D1 receptors inPFC. They demonstrated the quadratic relation between theimprovement of working memory capacity by training and thechange in D1 receptor binding induced by training, although great-er reduction in D1 receptor binding was associated with greaterimprovements in working memory capacity within the measuredrange (McNab et al., 2009). This might reflect down-regulation ofD1 receptors in response to a prolonged phasic dopamine releaseduring working memory training. If a D1 receptor antagonist/ago-nist radioligand with sensitivity for endogenous dopamine releasein PFC is developed, a more direct relationship between D1 recep-tors and PFC functions will be clarified. A D1 receptor agonist radi-oligand such as [11C]SKF 82957 is thought to be more sensitive toendogenous dopamine release, but in vivo imaging has so far notbeen successful (Palner et al., 2010).

4.2. Measurements of dopamine transmission beyond the synapse

Second, we should also consider beyond receptors. There havebeen some attempts to investigate second-messenger signaling be-yond synapse by PET. Cyclic adenosine monophosphate (cAMP) isone of the second messengers, and it plays an important role in neu-ronal signal transmission and transduction in the brain. Stimulationof D1 receptors elevates the level of cAMP by stimulating adenylatecyclase to convert adenosine triphosphate (ATP) to cAMP, whilestimulation of D2 receptors decreases the level of cAMP by inhibit-ing adenylate cyclase. cAMP-mediated signal transduction is termi-nated by degradation of cAMP to AMP by phosphodiesterase (PDE).Among subtypes of PDE, PDE4 selectively metabolizes cAMP in thebrain (Greengard, 1976). An inhibitor of PDE4, 4-[3-(cyclopent-oxyl)-4-methoxyphenyl]-2-pyrrolidone (rolipram) has been usedas a radiotracer for the quantification of PDE4 levels in the brain(Fujita et al., 2005). A previous study demonstrated that metham-phetamine increased PDE4 activity measured by [11C]rolipram inthe striatum of conscious monkey brain by stimulating D1 recep-tors (Tsukada et al., 2001). Recently, [11C]rolipram has been utilizedto investigate PDE4 activity in neuropsychiatric disorders. Using[11C]rolipram PET, widespread (including cerebral cortex and stria-tum) lower levels of PDE4 were reported in unmedicated depres-sion patients (Fujita et al., 2012). A previous [11C]SCH23390 PETstudy (Suhara et al., 1992) reported decreased prefrontal D1 recep-tors, and a [11C]NNC112 study (Cannon et al., 2009) reported de-creased striatal D1 receptors in depressed patients. We previouslyreported the relationship between dopamine receptors and presyn-aptic dopamine synthesis in the striatum combining [11C]racloprideand L-[b-11C]DOPA PET (Ito et al., 2011). A negative correlation wasobserved between the binding potential of dopamine D2 receptorsand endogenous dopamine synthesis rate in the striatum. Thus, thispoints to the necessity of investigating the relationship betweendopamine receptor density and second-messenger signaling be-yond receptors as well.

5. Conclusion

In conclusion, in order to understand the complex effects ofdopamine signaling on PFC functions, not only multi-facetedassessment of PFC functions containing various components withsubstantial overlaps, but also clever extraction and delineation ofeach component are needed. Equally, it certainly does not seem en-ough just to measure a single index related to basic dopamine tone.For a better understanding of the meanings of the PET indicesrelated to neurotransmitters, comprehensive information (presyn-aptic, postsynaptic, and beyond receptor signaling) will be re-quired. Still, an interdisciplinary approach combining molecularimaging techniques with cognitive neuroscience and clinical psy-chiatry will provide new perspectives for understanding the neuro-biology of neuropsychiatric disorders and their innovative drugdevelopments.

Acknowledgements

A part of this study is the result of ‘‘Integrated Research on Neu-ropsychiatric Disorders’’ carried out under the Strategic ResearchProgram for Brain Sciences by the Ministry of Education, Culture,Sports, Science and Technology of Japan (MEXT), a Grant-in-Aidfor Scientific Research on Innovative Areas: Prediction and Deci-sion Making (23120009), a Grant-in-Aid for Young Scientist A(23680045), a grant from the Smoking Research Foundation, a re-search grant from the Takeda Science Foundation, a research grantfrom the Brain Science Foundation, a research grant from the CasioScience Foundation and a research grant from the Senshin MedicalResearch Foundation.

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